The synthesis of the spiroalkanone-imide, 2,3-dihydrospiro-[naphthalene-1(4H), 3'-piperidine] -2',4,6'-trione, has been disclosed in the patent literature, i.e., Netherlands Pat. No. 6,411,613, and is said to be useful as an intermediate for the preparation of other compounds having diuretic, antihypertensive, and hypoglycemic properties. We have discovered that this compound and others of the present invention have central nervous system depressant properties and are useful as sedatives. The relatively non-toxic compounds of the present invention selectively inhibit spontaneous locomotor activity; that is, impaired motor coordination does not follow doses which reduce the motor activity. These substances also protect against the tonic extensor component of the maximal electroshock seizure and augment the central depressant effects of barbital and hexobarbital.
By way of illustration, 2,3-dihydrospiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione (Example 1), in mice, with an acute LD.sub.50 orally or intraperitoneally of over 2000 mg/kg reduced spontaneous locomotor activity in the photocell chamber (Dews, P. B., Brit. J. Pharmacol., 8: 46 (1953)) to 50 percent of control activity following doses of about 150 mg/kg orally or 50 to 60 mg/kg intraperitoneally. There is no significant impairment of motor coordination as determined with the rotorod method (Kinnard, W. J. and Carr, C. J., J. Pharmacol. Exptl. Therap., 121: 354 (1957)), on the other hand, until doses of 900 mg/kg, p.o. or 500-900 mg/kg i.p. have been administered. The dose which protects half the mice against maximal electroshock (Woodbury, L. A. and Davenport, V. D., Arch. Int. Pharmacodyn, 92, 97 (1952)) is estimated to be 120 mg/kg, p.o. and 160-170 mg/kg i.p. Loss of the righting reflex produced by appropriate doses of barbital or hexobarbital is significantly prolonged by doses of about 300 mg/kg i.p. of the test substance.
The spiroalkanone-imide, 6-chloro-2,3-dihydro-1'-methylspiro-[naphthalene-1(4H),3'-piperidine]-2',4 ,6'-trione (Example 18) is particularly useful as a sedative and has substantially greater activity than the known compound mentioned above as shown in the following table.
__________________________________________________________________________ Activities: All Values mg/kg (Mice) Anticonvulsant Spontaneous Locomotor Loss of Motor Protective Dose Activity: Depressant Coordination, 50% (Maximum Compound Dose 50% ED.sub.50 Electroshock) __________________________________________________________________________ Example 1 150, oral 900, oral 120, oral 50-60, i.p. 500-900, i.p. 160-170, i.p. Example 18 13, oral 285, oral __________________________________________________________________________